Management of women with premature ovarian insufficiency Guideline of the European Society of Human Reproduction and Embryology POI Guideline Development Group December 2015 1 Disclaimer The European Society of Human Reproduction and Embryology (hereinafter referred to as 'ESHRE') developed the current clinical practice guideline, to provide clinical recommendations to improve the quality of healthcare delivery within the European field of human reproduction and embryology. This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. The aim of clinical practice guidelines is to aid healthcare professionals in everyday clinical decisions about appropriate and effective care of their patients. However, adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not override the healthcare professional's clinical judgment in diagnosis and treatment of particular patients. Ultimately, healthcare professionals must make their own clinical decisions on a case-by-case basis, using their clinical judgment, knowledge, and expertise, and taking into account the condition, circumstances, and wishes of the individual patient, in consultation with that patient and/or the guardian or carer. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. ESHRE shall not be liable for direct, indirect, special, incidental, or consequential damages related to the use of the information contained herein. While ESHRE makes every effort to compile accurate information and to keep it up-to-date, it cannot, however, guarantee the correctness, completeness, and accuracy of the guideline in every respect. In any event, these clinical practice guidelines do not necessarily represent the views of all clinicians that are member of ESHRE. The information provided in this document does not constitute business, medical or other professional advice, and is subject to change. 2 CONTENTS Introduction to the Guideline 5 Summary 7 Interpretation on the grades of recommendations 7 List of all recommendations 8 PART A: Introduction to POI 1. Premature Ovarian Insufficiency (POI) 22 1.1 Nomenclature 22 1.2 Definition of Premature Ovarian Insufficiency 23 1.3 Prevalence of Premature Ovarian Insufficiency 26 PART B: Diagnosis of POI 2. Symptoms of POI 30 2.1 Symptoms of POI 30 3. Diagnosis and Initial assessment 32 3.1 Diagnosis of Premature Ovarian Insufficiency 32 3.2 Assessment of causation of Premature Ovarian Insufficiency 33 3.2.a POI caused by chromosomal and genetic defects 33 3.2.b POI caused by autoimmune ovarian damage 36 3.2.c POI due to infectious causes 41 3.2.d Iatrogenic causes of POI 41 3.2.e Environmental causes of POI 42 3.2.f Idiopathic POI 43 4. Implications for relatives of women with POI 47 PART C: Sequelae of POI 5. Life expectancy in women with POI 51 6. Fertility and pregnancy in women with POI 54 6.1 POI and consequences for fertility 54 6.2 Interventions for fertility in POI 55 6.3 Pregnancy in women with POI 58 6.4 Fitness for pregnancy in women with POI 62 7. Bone health in women with POI 67 7.1 POI and consequences for bone health 67 7.2 Interventions for bone health in POI 69 7.3 Monitoring bone health in POI 72 8. Cardiovascular health in women with POI 76 8.1 POI and consequences for the cardiovascular system 76 8.2 Estrogen replacement and cardiovascular risk factors in POI 78 8.3 Monitoring of cardiovascular risk factors 80 3 9. Quality of life in women with POI 85 9.1 POI and consequences for quality of life 85 9.2 Interventions for improving quality of life in women with POI 87 10. Sexual and genito-urinary function in women with POI 91 10.1 POI and consequences for sexuality 91 10.2 Interventions for sexuality in POI 93 10.3 Genito-urinary symptoms in POI 95 11. Neurological function in women with POI 99 11.1 POI and consequences for neurological function 99 11.2 Interventions for improving neurological function in POI 101 12. Hormone replacement therapy 107 12.1. Indications for HRT 107 12.2 Risks of HRT 109 12.2.a Breast cancer 110 12.2.b Endometrial cancer and endometrial hyperplasia 111 12.2.c Stroke 112 12.2.d Thromboembolic disease 112 12.3. HRT – treatment options 112 12.3.a Type of preparations: Estrogens and progestogens 113 12.3.b Regimens 114 12.3.c Route of administration 115 12.3.d Dose 117 12.3.e Duration 118 12.4. Monitoring HRT 119 12.5. POI women with special issues 120 12.5.a Women with Turner Syndrome 120 12.5.b Women with POI and a BRCA gene mutation or after breast cancer 121 12.5.c Women with POI and endometriosis 123 12.5.d Women with POI and other medical issues 123 12.6. Treatment with androgens 127 12.6.a Indications 128 12.6.b Risks of androgen therapy 129 12.6.c Routes of administration, dose, duration, monitoring 129 13. Puberty induction 138 14. Complementary treatments in POI 144 Appendix 1: Abbreviations 148 Appendix 2: Glossary 150 Appendix 3: Guideline group 152 Appendix 4: Research recommendations 154 Appendix 5: Methodology 156 Appendix 6: Reviewers of the guideline draft 160 4 INTRODUCTION TO THE GUIDELINE Previous guidelines At the time of the initiation of this guideline, Premature Ovarian Insufficiency [POI] was not addressed by existing guidelines. Comprehensive literature searching did not retrieve any guidelines specifically on the management of women with POI. Premature ovarian insufficiency has been included in several guidelines on infertility, but these mention POI only briefly, with the focus on infertility (National Institute for Health and Care Excellence, 2013) or menopause (de Villiers, et al., 2013). Guidance on management of Turner Syndrome was available but this concentrated on the other medical aspects of the syndrome and did not comprehensively address POI (Bondy and Turner Syndrome Study Group, 2007). Guideline development The Reproductive Endocrinology Special Interest Group of ESHRE initiated a guideline on POI. Membership of the Guideline development group was drawn from the Special Interest Group and the wider membership of ESHRE. Additional group members were recruited from outside ESHRE to contribute specialist expertise in certain topic areas (e.g. cardiology, neurology). A research specialist supported the guideline development. The members of the guideline development group are listed in Appendix 3. The scope of the guideline was determined by consensus. Guideline development followed a well-documented methodology, universal to ESHRE guidelines. The detailed methodology for this guideline is described in Appendix 5. Guideline scope This guideline offers best practice advice on the care of women with premature ovarian insufficiency, both primary and secondary. The patient population comprises women younger than 40 years (which includes Turner Syndrome patients) and women older than 40 years, but with disease onset before 40. The first chapters of this guideline will elaborate on the nomenclature and definition of premature ovarian insufficiency. Furthermore, this clinical guideline provides recommendations on the initial assessment and management of women with premature ovarian insufficiency. The initial assessment includes diagnosis, assessment of causation, and basic assessment. The management includes hormonal treatment. Since POI has consequences for health apart from gynaecological issues, these are also described. Consequences of POI and treatment options are included in the following domains: fertility and contraception, bone health, cardiovascular issues, psychosexual function, psychological function, and neurological function. Other topics discussed are puberty induction, life expectancy, and implications for relatives of women with POI. This guideline is limited to POI and does not apply to women with low ovarian reserve. Target users of the guideline The guideline covers the care provided by secondary and tertiary healthcare professionals who have direct contact with, and make decisions concerning the care of, women with premature ovarian insufficiency. ESHRE guidelines are mainly focussed on gynaecologists. However, women with POI suffer health problems that require multi- disciplinary care and are not limited to the field of gynaecology. Therefore, this guideline is also targeted at healthcare professionals of other disciplines (primary healthcare providers, endocrinologists, oncologists, 5 geneticists, paediatricians, internists). During the review phase and in development of tools for implementation, specific attention will be given to these healthcare professionals. This guideline is of relevance to European healthcare providers and women with premature ovarian insufficiency. For the benefit of patient education and shared-decision making, a patient version of this guideline will be developed. References Bondy CA, Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007;92: 10-25. de Villiers TJ, Pines A, Panay N, Gambacciani M, Archer DF, Baber RJ, Davis SR, Gompel AA, Henderson VW, Langer R, Lobo RA, Plu-Bureau G, Sturdee DW, International Menopause S. Updated 2013 International